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Sialylation in the Maintenance and Metabolic Plasticity of Neural Stem Cell-Like Brain Tumor Cells

唾液酸化在神经干细胞样脑肿瘤细胞的维持和代谢可塑性中的作用

基本信息

批准号：
10538769
负责人：
Anita Borton Hjelmeland
金额：
$ 50.6万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10538769
关键词：
ALCAM gene Adult Affinity Area Astrocytes Behavior Biological Assay Biology Brain Neoplasms Brain Pathology Cancer Biology Cell Communication Cell Differentiation process Cell Maintenance Cell Surface Proteins Cell Survival Cell membrane Cell surface Cells Cellular Metabolic Process Cessation of life Charge Chemoresistance Data Development Differentiation Antigens Enzymes GLUT-3 protein Genetic Glioblastoma Glucose Glucose Transporter Glycoproteins Golgi Apparatus Growth Growth Factor Receptors Human Integrins Lead Lectin Link Longitudinal Studies Maintenance Malignant Childhood Neoplasm Measures Mediating Mediator of activation protein Messenger RNA Metabolic Metabolism Modification Molecular Conformation Molecular Mechanisms of Action Mus Nature Neuronal Plasticity Neurons Neurosphere Nutrient Oligosaccharides Pathway interactions Pharmacology Phenotype Phosphorylation Polysaccharides Post-Translational Protein Processing Property Proteins Proteomics Publishing Research Resistance Role SLC2A1 gene Sialic Acids Sialyltransferases Signal Transduction Site Therapeutic Intervention Tumor Biology beta-galactoside cell growth cell motility differential expression effective therapy experimental study extracellular vesicles glucose uptake glycosylation improved inhibitor innovation inorganic phosphate insight knock-down metabolome migration mind control neoplastic cell nerve stem cell neurodevelopment novel nutrient deprivation paralogous gene protein expression protein function protein structure function receptor self-renewal sialylation stem stem cells stem-like cell temozolomide tumor growth tumor metabolism tumorigenic

项目摘要

PROJECT SUMMARY/ABSTRACT One of the least-investigated areas of research in brain pathologies is glycosylation, which is a critical regulator of cell surface protein structure and function. ST6Gal1 is the primary enzyme that a2,6 sialylates N-glycosylated proteins destined for the plasma membrane or secretion. Sialylation adds a negatively-charged, sialic acid to the end of an oligosaccharide chain of a glycoprotein. Sialylation of distinct protein subsets has important effects on conformation, clustering and cell surface retention as has been found for some integrins, growth factor receptors and death receptors. Through this mechanism, ST6Gal1 regulates phenotypes including survival, invasion, and stem cell maintenance. However, there are critical gaps in our understanding of how ST6Gal1-mediated sialylation impacts brain tumor cell growth or differentiation state, and there are no studies identifying a2,6 sialylated proteins or ST6Gal1 regulated pathways in brain tumors. Our preliminary data demonstrate a novel, pro-tumorigenic role for a2,6 sialylation and ST6Gal1 in the deadly brain tumor glioblastoma. We seek to determine whether ST6Gal1- mediated a2,6 sialylation promotes brain tumor initiating cell maintenance and metabolic plasticity. In the short- term, our results will lead to an improved understanding of how ST6Gal1-mediated a2,6 sialylation regulates protein expression and function to impact brain tumor propagation. In the long-term, these studies may offer the potential for new mechanisms of therapeutic intervention for the treatment of brain tumors as ST6Gal1 inhibitors are under development.

项目摘要/摘要在脑部病理学研究中最少被研究的领域之一是糖基化，它是一种关键的细胞表面蛋白的结构和功能。ST6Gal1是2，6唾液酸化N-糖基化的主要酶进入质膜或分泌的蛋白质。唾液酸化将带负电荷的唾液酸添加到糖蛋白低聚糖链的末端。不同蛋白质亚群的唾液酸化对一些整合素、生长因子受体的构象、聚集和细胞表面滞留已被发现和死亡感受器。通过这一机制，ST6Gal1调节表型，包括存活、侵袭和干细胞维护。然而，在我们对ST6Gal1如何介导唾液酸化的理解上存在着严重的差距影响脑肿瘤细胞的生长或分化状态，目前还没有研究确定2，6唾液酸化蛋白或ST6Gal1在脑肿瘤中的调控通路。我们的初步数据显示了一种新的促肿瘤作用 2，6唾液酸化和ST6Gal1在致死性脑瘤中的表达我们试图确定ST6Gal1- 介导的α-2，6-唾液酸化促进脑瘤起始细胞的维持和代谢可塑性。简而言之- 长期而言，我们的结果将有助于更好地理解ST6Gal1介导的2，6唾液酸化如何调节蛋白质表达和功能对脑肿瘤生长的影响。从长远来看，这些研究可能会提供寻找ST6Gal1抑制剂治疗脑肿瘤的治疗干预新机制发展。